The purpose of this invention is:                new selenohydroxy-acid compounds and their derivatives;        their process for the preparation;        their use as precursors of L(+)-selenomethionine and/or source of selenium in human or animal nutrition, in cosmetics and pharmaceutics;        and nutritional, cosmetic and pharmaceutical compositions containing them.        
State of the Art
This invention relates to new selenohydroxy-acids (SHA) and their derivatives, their preparations and applications in nutrition, cosmetics and pharmaceutics. More particularly, this invention relates to the synthesis of 2-hydroxy-4-methylselenobutyric acid, its salts and esters and amides derived from 2-hydroxy-4-methylselenobutyric acid as selenomethionine precursors and particularly L(+)-selenomethionine precursors according to a biomimetic approach using enzymes with animal or human origin.
Selenium is a micro-nutrient essential particularly for Man and mammals (Wendel, A.; Phosphorus, Sulfur Silicon Relat Elem.; 1992; 67, 1-4, 405-415). It participates in the biosynthesis of selenoproteins such as Glutathion peroxydase, as well as Thioredoxine reductase and Selenoprotein, in the form of L(+)-selenocysteine or L(+)-selenomethionine (Muller, S. et al.; Arch. Microbiol., 1997; 168; 421). According to FDA-RDAs 10th edition 1989 (Selenium: its molecular biology and role in human health; Hatfield, D. L. Eds; 2003; Kluwer Acad. Publishers; second edition; 299-31), Man's daily needs of selenium vary from 10-30 μg for a child to 40-70 μg for an adolescent-adult, these rates being higher particularly for women during pregnancy (65 μg/day) and during breast feeding (75 μg/day). The additional amount of L(+)-selenomethionine (2.7 μmoles of selenium equivalent) for breast feeding women significantly increases the concentration of selenium in their milk (McGuire, M. K. et al.; Am. J. Clin. Nutr.; 1993; 58; 5; 649).
Man is auxotrophic for L(+)-selenomethionine, which means that he is incapable of synthesising it. Therefore, the only way to obtain it is through food. Ideally, selenium should be absorbed in its natural form, in other words in organic form. Nevertheless, several forms of selenium may be used as a food complement; inorganic selenium for example such as sodium selenite; and organic selenium for example such as L(+)-selenomethionine. Knowing that more than 80% of total organic selenium in plants (particularly wheat, corn and soya) consists of L(+)-selenomethionine, this amino acid is the most appropriate and least toxic form of selenium, and is better than sodium selenite as an animal or human food complement (Schrauzer, G. N.; J. Am. Coll. Nutrit.; 2001; 20; 1; 1-4). L(+)-selenomethionine has better bio-availability and is much better tolerated than sodium selenite (Mony, M C et al.; J. of Trace Elem. Exp. Med.; 2000; 13; 367-380).
L(+)-selenomethionine has anti-oxidative properties due to the presence of selenium in its molecular structure (Tapiero H et al.; Biomed. Pharmacother.; 2003; 57; 3-4; 134-144). It has been shown that L(+)-selenomethionine very effectively traps peroxynitrite, an extremely toxic metabolite generated in all inflammatory situations and for which the deleterious action causes cell death (Assman, A. et al.; Arch. Biochem. Biophys.; 1998; 349; 201-203).
A selenium food complement proved to be very beneficial in many situations (nutritional deficiency, diseases, exposure to radiation, etc.). This is particularly true for children suffering from genetic diseases such as phenylcetonuria or hyperphenylalaninemia, since these children have low protein diets (Reilly, C. et al.; Am. J. Clin. Nutr.; 1990; 52; 150-165). Selenium in organic form such as L(+)-selenomethionine associated with vitamins has protective effects with regard to UV radiation in man (La Ruche et al.; Photodermtol. Photoimmunol. Photomed.; 1991; 8; 6; 232-235). L(+)-selenomethionine protects against the deleterious biological effects of high energy ionising radiation (Kennedy, A R et al.; Free Rad. Biol. Med.; 2004; 36; 2; 259-266).
Furthermore, several organoselenium derivatives have been effective in the prevention of some types of cancer in Man. In this context, it has been shown that L(+)-selenomethionine causes activation of a DNA repair system, mediated by the p53 tumour suppressor, thus reducing the accumulation of mutations in somatic cells (Seo, Y R et al.; PNAS; 2002, 89; 22;14548). It has been shown that a complement of up to 200 μg/Se/day of L(+)-selenomethionine in Man very significantly reduces the incidence of cancers such as cancer of the lungs, colorectal cancer and prostate cancer. Seven out of a total of eight clinical tests to evaluate the effect of selenium on the incidence of cancer gave positive results (Whanger, P D; Br. J. Nutr.; 2004; 91, 1, 11-28). This confirms the many studies carried out on animals.
Some rare selenohydroxy-acid derivatives have already been described as synthetic intermediates in the preparation of organic derivatives. These are essentially arylselenohydroxy-acid derivatives. For example, this is the case for the methyl ester of 2-hydroxy-4-phenylselenobutyric acid (J.-G. Boiteau, Organic Letters, 2001, 3 (17), 1737-2740). Furthermore, a selenoxide of 2-hydroxy-4-methylselenobutyric acid has been suggested as an intermediate of oxydative degradation of L(+)-selenomethionine (Gammelgaard, B. et al.; Talenta; 2003; 59; 1165-1171).
Surprisingly, 2-hydroxy-4-methylselenobutyric acid itself, its salts and its ester and amide derivatives, are not known. Unlike arylselenohydroxy acid derivatives, these latter compounds may represent potential precursors of selenomethionine. After an enzymatic or chemical transformation, 2-hydroxy-4-methylselenobutyric acid, its salts and its ester and amide derivatives, after eventual hydrolysis, can lead to selenomethionine according to the following transformation

Furthermore, 2-hydroxy-4-methylsulfobutyric acid is known as a methionine precursor for food (WO 9636598; 21 Nov. 1996).
One of the purposes of this invention is to create new compounds containing selenium that, after being administered to man or to animal, may be precursors of selenomethionine, and therefore sources of selenium for the organism. Compounds according to the invention can penetrate inside tissues or cells to be biotransformed into selenomethionine or derivatives so that selenium can be incorporated into proteins of the organism.
These purposes are achieved through this invention that is based on the design of new selenohydroxy-acid derivatives and their esters and amides, which are biotransformed by enzymes present in animal or human cells to generate selenomethionine. This has been exemplified by the Applicant.